Scientists and clinicians face a number of challenges in their attempts to develop active agents into forms suited for delivery to a patient. Active agents that are polypeptides, acid-labile active agents, or agents with low oral bioavailability are often delivered via injection rather than the oral route. In this way, the active agents are introduced into the systemic circulation without exposure to the acidic environment of the stomach. However, delivery of active agents via injection may lead to rapid clearance by kidney and/or liver. Thus, delivery of active agents is often problematic even when these agents are administered by injection.
Some success has been achieved in addressing the problems of delivering active agents via injection. For example, conjugating the active agent to a water-soluble polymer has resulted in polymer-active agent conjugates having reduced immunogenicity and antigenicity. In addition, these polymer-active agent conjugates often have greatly increased half-lives compared to their unconjugated counterparts as a result of decreased clearance through the kidney and/or decreased enzymatic degradation in circulation. As a result of having greater half-life, the polymer-active agent conjugate requires less frequent dosing, which in turn reduces the overall number of painful injections and inconvenient visits to a health care professional. Moreover, active agents that are only marginally soluble often demonstrate a significant increase in water solubility when conjugated to a water-soluble polymer.
Due to its documented safety as well as its approval by the FDA for both topical and internal use, polyethylene glycol has been conjugated to variety of active agents. Despite these successes, conjugation of a water-soluble polymer to an active agent remains challenging. One such challenge is the deactivation of the active agent upon attachment to a relatively long polyethylene glycol molecule. Although a relatively long polyethylene glycol molecule would provide the corresponding active agent-polymer conjugate with greater water solubility, conjugates bearing such long polyethylene glycol moieties have been known to be substantially inactive in vivo. It has been hypothesized that these conjugates are inactive due to the relatively long polyethylene glycol chain, which may “wrap” itself around the entire active agent, thereby blocking access to potential ligands required for activity.
It would be desirable, therefore (among other things), to be able to provide conjugates such that their hydrolysis rates could be “customized.” For example, with respect to the typical weekly administration of PEGylated interferon alpha-2a, a slower rate of hydrolysis might provide for even longer periods between administrations. In addition, conjugates having too long of an in vivo half life could be improved by increasing the conjugates' susceptibility to hydrolysis.
Thus, there is a need in the art to provide reagents with different reactivities to expand the possible repertoire of active agent-conjugates.
The present invention seeks to address these and other needs in the art.